Parkinson's disease is a difficult-to-treat, progressive disorder which is the second most common neurodegenerative disease, and is socially and economically problematic because its incidence rate continues to rise as the population of seniors increases. Currently, about 4 million people worldwide are known to have the disease, and it is understood that the number of new cases per year is growing by about 50 thousand in U.S. alone. The incidence rate of one in 1,000 is more prevalent-in older age groups. The disorder is known to be mostly associated with aging, environmental factors such as neurotoxin accumulation from agricultural chemicals, etc., active oxygen, genetic factors (about 5% to about 10%), etc are known to have effects on the incidence. However, the exact cause of incidence is unknown. As for genetic factors, gene mutations such as α-synuclein, Parkin, PINK-1, UCH-L1, DJ-1, etc. are known to be associated with incidence.
Anatomical studies show that Parkinson's disease is associated with a broad range of degeneration of dopaminergic substantia nigra neurons located in the basal ganglia of the brain. When about 60% to about 80% of the amount of dopamine produced by substantia nigra neurons is damaged, it can no longer facilitate the movement of the extrapyramidal tract system, thereby resulting in Parkinson's symptoms.
Because the exact cause of Parkinson's disease has not been determined, treatment methods for ameliorating symptoms are usually used, rather than fundamental cures. Therapeutic agents currently used or under development are as follows. Drugs which are predominantly developed and used include dopamine precursors such as Levodopa as a dopamine supplement and dopamine receptor agonists such as Fenofibrate. In addition, COMT inhibitors which maintain the dopamine concentration in the brain by inhibiting dopamine metabolism and MAO-B (monoamine oxidase B) inhibitors are being used. As a neurotransmitter enhancing drug besides dopamine, antimuscarinics and NMDA antagonists are developed and used, and continuous efforts are being made to use or develop neuronal protective agents, antioxidants, inhibitors of neuronal apoptosis, and agonists for brain function as therapeutic agents. Surgical therapies such as deep brain stimulation are applied to terminal stage patients who can no longer benefit from drug therapies.
Selegiline (Deprenyl) as a MAO-B inhibitor has been used as a drug for treating Parkinson's disease and is considered a gold standard. However, its use has many limitations due to hepatotoxicity and production of metamphetamine as a metabolite. Azilect (Rasagiline) was first commercially introduced in Europe in 2005 and approved by the US FDA in 2006 as a new MAO-B inhibitor, and emerged as a new therapeutic agent for Parkinson's disease that overcomes the disadvantages of Selegiline. If clinical tests can verify that Azilect has neuronal protective effects that other current therapeutic agents lack, the value of the drug as a new therapeutic agent will be greatly enhanced.
However, because both Selegiline and Rasagiline are irreversible MAO-B inhibitors, they may inhibit the activity of MAO-B until new MAO-B is produced in vivo, thereby increasing the possibility of unpredictable side effects. As an alternative to make up for these shortcomings, a new drug to show potent enzyme inhibitory activity in a reversible manner is expected to be superior to conventional irreversible inhibitors in terms of safety and efficacy. While a reversible MAO-B inhibitor called Safinamide has been developed and is under clinical testing (Phase III), an exceptional reversible MAO-B inhibitor has not been developed yet.